PRECLINICAL STUDY: The effects of p-chloroamphetamine, methamphetamine and 3,4-methylenedioxymethamphetamine (ecstasy) on the gene expression of cytoskeletal proteins in the rat brain

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Repeated administration of β-phenylalkylamines is known to produce neuronal changes in the central and peripheral nervous systems of mammals. It is suggested that various components of the cytoskeleton undergo profound alterations after amphetamine use and misuse, contributing to behavioral changes and neurotoxicity. Here we studied the expression of microtubule-associated protein 2 (MAP2) and β-actin after repeated intraperitoneal applications with equimolar doses of p-chloroamphetamine (PCA), methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA) in the brain of male Wistar rats. Effective (molecular) pharmacological doses (ED) were derived and used for the calculation of (molecular) pharmacological indices (PI). Besides clear but different dose–response curves on the toxicity of the drugs, in situ hybridization and Western blot analysis revealed that repeated administration of these compounds resulted in different substance- and dose-dependent changes in MAP2 gene expression, e.g. in the frontoparietal somatosensoric cortex. In contrast, the expression of β-actin was not influenced by any of the compounds at the dose levels tested. Lethal doses were determined with 2.1 (PCA), >5.1 (METH) and 8.4 mg/kg/day (MDMA). Linear and non-linear repeat-dose lethality was observed for MDMA and PCA, respectively, whereas METH was non-lethal in the dose range used. Values for EDMAP2 were 0.3, 0.52 and >16.8 mg/kg/day, and therefore those for PIMAP2 were 20, 4, and 0.5 for METH, PCA and MDMA, respectively. Although the results on mortality did not reflect changes in MAP2 gene expression, they suggest a remarkable difference for those amphetamines without substituents or with a halogen atom at the paraposition of the benzene ring, such as METH or PCA, when compared with MDMA-like substances.

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